PROJECT SUMMARY Alaska Native infants from Western and Northern Alaska historically have had among the highest incidences ever documented of severe illness due to infectious disease, as well as an infant mortality rate more than twice that in other parts of Alaska. We have shown that one of the factors responsible for these health disparities is a single nucleotide variant in the carnitine palmitoyltransferase 1A (CPT1A) gene (c.1436C>T; p.P479L), which we have named the arctic variant of CPT1A. The arctic variant was first identified in the Alaska Native population in 2003 following the implementation of expanded newborn screening by tandem mass spectrometry, and has been shown to be the most common form of the CPT1A gene in the Yup'ik and Inupiaq Alaska Native people of Western and Northern Alaska (gene frequency = 0.7), as well as other indigenous arctic populations in Canada, Greenland, and Siberia. Since it was first identified, there have been a variety of efforts undertaken in both Alaska and Canada to understand the potential health effects associated with the arctic variant. Although much has been learned, there remain significant gaps in our knowledge. The high prevalence of the arctic variant in arctic populations is the result of positive genetic selection, hypothesized to have resulted from beneficial effects to people living in a cold environment and consuming a traditional subsistence diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs). Beneficial health effects have been demonstrated in adults from Western Alaska and Greenland, which is in stark contrast to our observations that infants with two copies of the arctic variant are at increased risk for infectious diseases, and infant mortality. We believe that the detrimental effects of the arctic variant are a consequence of changes in diet, including reduced intake of traditional foods rich in n-3 PUFA. We hypothesize that n-3 PUFA status modifies the health effects of the variant, such that risks associated with homozygosity for the variant will be lowest in infants with the highest n-3 PUFA levels. To test this hypothesis, we have assembled a team of investigators from the Alaska Native Medical Center and Oregon Health & Science University, with PIs at each location, to undertake a prospective cohort study of Alaska Native children that will begin prenatally and continue through the first 2 years of life. In Aim 1, we will prospectively characterize the health effects of the CPT1A arctic variant in Alaska Native infants. Aim 2 will explicitly test the gene-diet hypothesis by evaluating the impact of pre- and postnatal exposure to n-3 PUFAs on the health effects of the CPT1A arctic variant. In Aim 3, data from Aims 1 & 2 will be used to develop and evaluate a risk prediction model that identifies and quantifies the contribution of CPT1A genotype, n-3 PUFAs, and other risk factors to infectious disease-related infant outcomes. The primary study objective is to translate results into evidence-based recommendations for infants identified by newborn screening to have two copies of the CPT1A arctic variant.